CN108671232A - A kind of combination preparation that can reduce internal acetaldehyde concentration and preparation method thereof and purposes - Google Patents

A kind of combination preparation that can reduce internal acetaldehyde concentration and preparation method thereof and purposes Download PDF

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CN108671232A
CN108671232A CN201810742665.8A CN201810742665A CN108671232A CN 108671232 A CN108671232 A CN 108671232A CN 201810742665 A CN201810742665 A CN 201810742665A CN 108671232 A CN108671232 A CN 108671232A
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acetaldehyde
preparation
combination preparation
probiotics
combination
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谢苍桑
张利鹏
张溪之
徐畅
李军华
姜长安
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Zhuhai Zhongke Advanced Technology Research Institute Co Ltd
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Abstract

The invention discloses a kind of combination preparation that can reduce internal acetaldehyde concentration and preparation method thereof and purposes, the combination preparation includes at least a kind of acetaldehyde-binding compound containing one or more free sulfhydryl groups and amino, a kind of probiotics with acetaldehyde metabolic capability and a kind of carrier, the combination preparation can be used for preparing relieve the effect of alcohol, protect liver, the food, drug or the health products that protect lung and treatment or prevention oral cavity, pharynx, oesophagus, stomach, lung, liver or large intestine cancer drug in.Compared with prior art, resistance to wine ability is relieved the effect of alcohol or promoted to the program by reducing acetaldehyde concentration and can realize, has a good application prospect.

Description

A kind of combination preparation that can reduce internal acetaldehyde concentration and preparation method thereof and purposes
Technical field
The present invention relates to biomedicine technical fields, and in particular to a kind of combination preparation that can reduce internal acetaldehyde concentration And preparation method thereof and purposes.
Background technology
In organism, most ethyl alcohol are acetaldehyde by oxidative metabolism in liver, and fraction ethyl alcohol is by alimentary canal (saliva Gland, oral cavity and gastrointestinal tract mucous cell) and its microbial metabolism be acetaldehyde.Ethyl alcohol is absorbed in alimentary canal, is enriched in alimentary canal Blood circulation oxidation of ethanol is quickly metabolized as by the aerobic bacteria being colonized herein, facultative anaerobic bacteria and alimentary canal endothelial cell Acetaldehyde, but they are metabolized the poor ability of acetaldehyde.Therefore, alimentary canal becomes the important aggregate site of internal acetaldehyde.Such as it is tying Rectum, enterobacteriaceae is highly enriched, huge number, and the alcohol dehydrogenase activity of some bacteriums is even also than the alcohol dehydrogenase of liver Much higher, this position acetaldehyde concentration is linear related to ethyl alcohol, becomes the localized clusters position of acetaldehyde after drinking.Secondly, alcohol drink The acetaldehyde contained in itself in material be also drink the raised important sources of metenteron part acetaldehyde (Lachenmeier et al., (2008)Food Chem Toxicol 46(8):2903-2911), and its illeffects is significantly larger than produced by alcohol metabolism Acetaldehyde.Therefore, highest acetaldehyde is present in large intestine and saliva in person's body of drinking pick-me-up.
Studies have shown that acetaldehyde toxicity is 30 times of ethyl alcohol, chemical property is more active than ethyl alcohol, can be with each hatching egg of intraor extracellular White matter combines, and forms acetaldehyde-protein product, destroys the structure and property of protein, keeps certain enzymatic activitys reductions or activity complete It is complete to lose, it is ineffective and dead to can also result in certain tissues.Acetaldehyde can form adduct, this adduction with internal DNA simultaneously The startup factor that object will occur as cancer.Since the strong carcinogenicity of acetaldehyde and its acetaldehyde caused by drinking and (or) smoke etc. expose Position feature, cause the positions such as oral cavity, pharynx, oesophagus, stomach, liver, mammary gland and large intestine cancer occur high risk.In view of second Aldehyde is not only present in alcoholic beverage and tobacco, is also widely present in food, industry and environment, is that the mankind are most common carcinogenic Substance, and it is public on the cognition of acetaldehyde and its potential public health influence between there is huge knowledge wide gaps, lead to mesh Preceding research is not yet able adequately determines acetaldehyde to public risk size.
For drinking, the uncomfortable reaction that alcohol user is likely to occur includes blushing, and heartbeat is overrun, and blood pressure declines, and nausea is vomitted It spits, headache and dizzy, is unable to freedom of movement, phenomena such as severe patient is likely to occur and is still drank after a night (common sympton be headache, tired and dehydration). Generally, it is considered that these discomfort reactions are that contained acetaldehyde and ethyl alcohol are metabolized as caused shadow after acetaldehyde in vivo in alcoholic beverage It rings.
Aldehyde dehydrogenase 2 (acetaldehyde dehydrogenase, ALDH2) is that degradation acetaldehyde is most important in body Enzyme, active power are largely fixed the acetaldehyde harm to the human body size in the sources such as drink and (or) smoke.ALDH2 is main Expression is not expressed even seldom in liver in the expression at the positions such as including alimentary canal.ALDH2 lacks type living and shows blood after drinking Acetaldehyde concentration increases notable, the features such as flush and tachycardia in liquid, this is because acetaldehyde has Rapid Expansion capillary The effect of blood vessel.Since the characteristic of high genetic polymorphism is distributed, the ALDH2 of about 40% gook shows as lacking type living, no Acetaldehyde in the timely and effective metabolism body of energy, internal acetaldehyde accumulation is in the part such as oral cavity, pharynx, oesophagus, stomach, liver or large intestine, several times Ground increases risk (Salaspuro et al., (2003) Best Pract Res Clin that these position cancers occur Gastroenterol 17(4):679-694).Nevertheless, ALDH2, which lacks genotype person living, is still likely to become alcoholic, even Develop into alcohol dependence patient.Excessive alcohol intake causes body in disorder, and long-term excessive drinking is to nervous system and liver Dirty damage is especially serious, and significantly improves the occurrence risk of alimentary canal related neoplasms.Ethyl alcohol in alcoholic beverage itself is not Have a carcinogenicity, but its oxidation metabolites acetaldehyde have high toxicity, mutagenicity and strong carcinogenicity (Salaspuro et al., (2003)Crit Rev Clin Lab Sci 40(2):183-208).Accordingly, it is possible to the ethyl alcohol pole being present in oral cavity or stomach It is possible that because being metabolized as after acetaldehyde constantly accumulate to reach carcinogenic level in saliva and gastric juice.
Probiotics is the non-pathogenic microorganisms that can adjust human body microecological balance：They are by improving enteric microorganism bacterium Group secretes anti -inflammatory cytokine, improves intestinal barrier integrity, and reduces the release of proinflammatory cytokines etc. of harmful bacteria generation, To play effect (Hartmann et al., (2012) Front Physiol 3 for promoting host health:402).Wherein to sandlwood The most study of sugared lactobacillus, is most widely used.Probiotics has obtained many animals to the therapeutic effect of alcoholic liver disease and has tried It tests and clinical experimental study evidence.At present have in this respect the probiotics of application include Bifidobacterium, lactic acid bacteria, Propionibacterium, Gram Escherichia coli Neisseria etc..Many facultative anaerobic bacterias and aerobic bacteria have higher alcohol dehydrogenase in human body alimentary canal Activity, but then type is less for the bacterium with aldehyde dehydrogenase activity.The bifid bar of wherein micro- aerobic-type Bacillus acidi lactici and anaerobic type Bacterium has different degrees of aldehyde dehydrogenase activity.This two classes bacterium is important the intrinsic bacterium of enteron aisle, and density is high in big intestinal contents Up to 1011-1014CFU/g.Studies have shown that 53103 plants of Lactobacillus rhamnosus ATCC has higher acetaldehyde-dehydrogenase in this two classes bacterium Enzymatic activity and lower aldehyde dehydrogenase activity (NOSOVA et al., (2000) Alcohol＆Alcoholism 35 (6):561- 568)。
Lactobacillus rhamnosus (lactobacillus rhamnosus, LGG) belongs to gram-positive bacteria, nineteen eighty-three by Bostonian two scientists Sherwood Gorbach and Barry Goldin is separated from human excrement and urine, can be attached to Intestinal mucosa and intestinal epithelia, the bacterium are primarily present in human body large intestine.The bacterium has outstanding gastrointestinal tract survival ability；Energy Antibacterial material is generated, the sense of the harmful bacterias such as salmonella, staphylococcus aureus, Listeria, helicobacter pylori can be resisted Dye；It can effectively stick and protect intestinal epithelial cell, improve the integrality of gut barrier, adjust immune response；There is provided part and Systemic health benefits.The long-term rat for feeding alcohol can be substantially reduced in it after in feeding, supplement is with probiotics LGG Endotoxemia symptom and alcohol-induced Experimental Hepatic Damage (Nanji et al., (1994) Proc Soc Exp Biol Med 205(3):243-247).53103 bacterium of LGG ATCC have both alcohol dehydrogenase and aldehyde dehydrogenase activity：Can be by alcohol metabolism Acetaldehyde, and acetaldehyde is metabolized as acetic acid.Moreover, its aldehyde dehydrogenase activity is significantly higher than alcohol dehydrogenase activity.In 22mM second Under conditions in vitro existing for alcohol, the speed that oxidation of ethanol is metabolized as acetaldehyde by 53103 bacterium of LGG ATCC is 80nmol/109CFU/ ml；And under the conditions in vitro existing for 500 μM of acetaldehyde, acetaldehyde metabolic rate reaches 359nmol/109CFU/ml, acetaldehyde of degrading Ability have outstanding performance in known lactobacillus and Bifidobacterium class probiotics (NOSOVA et al., (2000) Alcohol＆ Alcoholism 35(6):561-568).With this metabolism state, even if drinking under state really, same concentrations LGG 53103 bacterium of ATCC are in human body metabolism's ethyl alcohol for acetaldehyde until the rate of acetic acid all will be high.Therefore, most preferably, with LGG ATCC 53103 is as the probiotics for reducing internal acetaldehyde.
N-acetyl-L-cysteine (N-acetylcysteine, NAC) is naturally occurring amino acid L-cysteine The derivative of acetylation, it has reproducibility group sulfydryl, can react to form imines substance (2- methyl tetrahydrochysene thiophenes with acetaldehyde Azoles -4- carboxylic acids) (2-methyl-thiazolidine-4-carboxylic acid, MTCA), the substance is relatively stable, and nothing Poison can be expelled directly out external.Therefore, NAC can effectively release acetaldehyde toxicity.In addition to this, NAC can occur with free radical Reaction, and then remove the free radical generated when metabolism ethyl alcohol.It can also be converted into Guang ammonia object, repair damaged tissues.
Therefore, if NAC and LGG can be combined for reducing internal acetaldehyde concentration the energy of resistance to wine is relieved the effect of alcohol or improves to realize Power, it would be possible to obtain good effect, however there has been no relevant reports in the prior art.
Invention content
The technical problem to be solved by the present invention is to：There is provided a kind of combination preparation that can reduce internal acetaldehyde concentration and its Preparation method and purposes, which can either alleviate the uncomfortable reaction such as digestive system after drinking and nervous system, and can drop Low oral cavity and alimentary canal lead to the risk that cancer occurs because of acetaldehyde.
In order to solve the above-mentioned technical problem, the technical solution adopted by the present invention is：One kind can reduce internal acetaldehyde concentration Combination preparation, include at least a kind of acetaldehyde-binding compound containing one or more free sulfhydryl groups and amino, a kind of tool There are the probiotics of acetaldehyde metabolic capability and a kind of carrier.
Further, the acetaldehyde-binding compound includes but not limited to cysteine and its derivative and reduced form paddy The sweet peptide of Guang.
Preferably, the cysteine is L-cysteine or D-Cys.
Preferably, the cysteine derivative includes D, L- homocysteine and H- Cysteine-Glycines-OH.
Further, the probiotics with acetaldehyde metabolic capability be with aldehyde dehydrogenase activity, can be in human body It is colonized and the probiotics for internal acetaldehyde of degrading.
Preferably, the probiotics with acetaldehyde metabolic capability includes lactobacillus and Bifidobacterium.
Further, the lactobacillus includes Lactobacillus brevis and lactobacillus acidophilus；The Bifidobacterium includes two pairs of branch bars Bacterium and other Bifidobacteriums.
It is highly preferred that the probiotics with acetaldehyde metabolic capability is LGG.
Further, the Lactobacillus rhamnosus is to be preserved in American Type Culture collection warehousing (American type Culture collection, ATCC) bacterial strain, deposit number be ATCC 53103.
Further, the quality of the carrier is the 10~50%, preferably 15~40% of the combination preparation gross mass, More preferably 20~30%.
Further, the carrier is polymer soluble in the stomach.
Preferably, the carrier includes methacrylate derivative, chitosan, alginates, aluminium hydroxide, carbon Sour hydrogen sodium, sodium carboxymethylcellulose, sodium bicarbonate, carbomer and skim milk, more preferably methacrylate derivative, most Preferably Eudragit L and Eudragit S.
Preferably, the content of the sodium bicarbonate is the 10~30% of the carrier, preferably 20%.
Further, in the combination preparation, the quality of the acetaldehyde-binding compound is at least 500mg, the tool There is the quantity of the probiotics of acetaldehyde metabolic capability to be no less than 30,000,000,000 (3 × 1010CFU)。
Further, the dosage form of the combination preparation is tablet, capsule and/or particle.
Preferably, the preparation of the acetaldehyde-binding compound is formed as tablet, particle or capsule, described to have acetaldehyde generation The preparation for thanking to the probiotics of ability is formed as capsule.
The beneficial effects of the present invention are：In acetaldehyde-binding compound containing sulfydryl and amino in the present invention program, Free sulfydryl and amino all has the function being combined with acetaldehyde, and when it is reacted with acetaldehyde, acetaldehyde can be with its sulfydryl and ammonia Base junction is closed, generation 2- methyl-L- thiazolidine -4- formic acid (2-methyl-L-thiazolidane-4-formic acid, MTCA), and MTCA is to human body that there is no damaging effects, after being directly dissolved in water, is excreted with urine；The present invention program is ingenious Acetaldehyde-binding compound and probiotic group synthesis group are closed preparation by ground, and said preparation can be reacted and be tieed up with acetaldehyde in vivo rapidly The long period is held, acetaldehyde is metabolized as innocuous substance and is excreted, the present invention program combination preparation can office in a long time Portion combines and the acetaldehyde in human body of degrading, so that acetaldehyde keeps below harmful limit or less than without using the medicine in vivo Content at least 30% or more when compositions；Carrier in the present invention program is for controlling releasing for the acetaldehyde-binding substances Speed is put, so that release time is at least 1 hour acetaldehyde-binding substances under one's belt.The present invention program combination preparation is to local generation Thanking to raised acetaldehyde has good effect, the acetaldehyde that combination preparation of the present invention is applicable to reduce any approach source in vivo dense Degree, is used especially for reducing that the gastrointestinal tract because drinking caused by and nervous system etc. are uncomfortable to react, the generation due to acetaldehyde with drink Pick-me-up amount is related, and therefore, the present invention program can also promote alcohol user's capacity for liquor level, while the present invention program can also reduce The probability that cancer occurs in oral cavity and alimentary canal.
The invention also includes the preparation methods of said combination preparation, and the preparation method comprises the following steps：
S1, the probiotics with acetaldehyde metabolic capability is used to microencapsulation, dry embedding techniques or double-layer embedment Technology is prepared into capsule preparations；
S2, the acetaldehyde-binding substances are prepared into coating tablet, granular preparation or capsule preparations；
S3, by with acetaldehyde metabolic capability after the step S1 and S2 operation processings probiotics and bind acetaldehyde object Matter mixes up to the combination preparation；
Wherein, the operation order of the step S1 and step S2 can be carried out at the same time, also interchangeable.
Further, the coating of the coating tablet is the polymer soluble in the stomach that can be hydrolyzed under one's belt.
Preferably, amount of the polymer soluble in the stomach in combination preparation gross mass is 5~20%.
Further, the granular preparation includes the acetaldehyde-binding substances being coated by clothing soluble in the stomach.
Further, the granular preparation further includes filler and adhesive.
Further, described adhesive is polymer soluble in the stomach, and the polymer soluble in the stomach can hydrolyze under one's belt and the stomach The quality of insoluble polymer accounts for the 2-5% of the granular preparation quality, it is preferable that the quality of the polymer soluble in the stomach is the particle The 3~4% of the quality of the pharmaceutical preparations.
Further, the component for including following weight point in the granular preparation：60 parts of acetaldehyde-binding substances, de- second 0~30 part of 10~40 parts of acyl chitin and calcium monohydrogen phosphate.
Preferably, the probiotics is prepared into capsule preparations using dry embedding techniques.
Further, the preparation method further includes the preparation of probiotics powder, the preparation process of the probiotics powder It is as follows：
The probiotics viable bacteria body of S101, culture with acetaldehyde metabolic capability, and by the benefit with acetaldehyde metabolic capability Raw bacterium viable bacteria body is detached from culture solution；
S102, the step S101 isolated probiotics viable bacteria body with acetaldehyde metabolic capability through culture, fermentation, After concentration operation, after stabilizer, then freeze-dried operation is added, probiotics powder is obtained.
The advantageous effect of the present invention program is：The combination preparation discharges bind acetaldehyde object with sustained release fashion under one's belt Matter, invention formulation are carried the combination preparation substance to stomach by carrier, then make combination substance release.Reagent is whole or big portion Be divided into tablet, capsule or particle, be adhered to when it is wetted under the influence of hydrochloric acid in gastric juice acetaldehyde-binding substances in gastric mucosa or Person is formed in floating in the content of stomach and agglomerates so that residence time extends under one's belt for it, thus makes the release of drug With to the local action of stomach extension, by with acetaldehyde metabolic capability probiotics and acetaldehyde-binding substances dosage form Control, to the release of active ingredient in control combination preparation.For probiotics, microencapsulation, double-layer embedment technique can be used The key technology of the industrialization production of composition；Microencapsulation protection technique efficiently solves oral process high temperature and strong acid Inactivation of the gastric juice to probiotics；Using double-layer embedment microcapsules technology, is conducive to probiotics and passes through gastric juice by oral and arrive The effect of stopping field planting in up to enteron aisle, making product greatly improves compared with the similar product of market.
The invention also includes said combination preparation prepare relieve the effect of alcohol, protect liver, protect lung food, drug or health products and controlling Treat or prevent oral cavity, pharynx, oesophagus, stomach, lung, liver or large intestine cancer drug in purposes.
The advantageous effect of the present invention program is：Combination preparation of the present invention is applicable to the consumption containing a large amount of alcoholic beverage Person is particularly suitable for those of ALDH2 low activities；Combination preparation of the present invention is also beneficial to the pick-me-up of consumption moderate quatity Consumer or consumer of the consumption containing a small amount of alcohol or acetaldehyde food；It is additionally beneficial to smoker simultaneously；Due to containing in tobacco A large amount of acetaldehyde, in smoking process, acetaldehyde concentration steeply rises in human body upper digestive tract, the combination preparation in addition to can effectively and When eliminate internal acetaldehyde, also to gastrointestinal tract have important protective effect, intestinal epithelial cell can be protected by being embodied in, improve The integrality of gut barrier, adjust immune response, reduce due to harmful bacteria release lipopolysaccharides (lipopolysaccharide, LPS level of endotoxin in blood caused by).Since smoking can lead to the unbalance of human body Tiny ecosystem, cause micro- life harmful to health Object increases, and beneficial flora is reduced, and therefore, combination preparation of the present invention can have good effect in terms of protect liver protects lung.
Description of the drawings
Fig. 1 is In vitro metabolism acetaldehyde ability and reaction time of the combination preparation made from the embodiment of the present invention with control group one Relational graph；
Fig. 2 is the In vitro metabolism of combination preparation and control group two made from the embodiment of the present invention containing ethyl alcohol Acetaldehyde ability and reaction time relational graph；
Fig. 3 is the internal test result statistical chart of combination preparation made from the embodiment of the present invention.
Specific implementation mode
To explain the technical content, the achieved purpose and the effect of the present invention in detail, below in conjunction with embodiment and coordinate attached Figure is explained.
A kind of combination preparation that can reduce internal acetaldehyde concentration includes at least a kind of containing one or more free sulfhydryl groups With acetaldehyde-binding compound, a kind of probiotics with acetaldehyde metabolic capability and a kind of carrier of amino.
As can be seen from the above description, the beneficial effects of the present invention are：Acetaldehyde knot containing sulfydryl and amino in the present invention program In conjunction property compound, free sulfydryl and amino all have the function being combined with acetaldehyde, when it is reacted with acetaldehyde, acetaldehyde It can be combined with its sulfydryl and amino, generate 2- methyl-L thiazolidine -4- formic acid (2-methyl-L-thiazolidane-4- Formic acid, MTCA), and MTCA is to human body that there is no damaging effects, after being directly dissolved in water, is excreted with urine；This Acetaldehyde-binding compound and probiotic group synthesis group are dexterously closed preparation by scheme of the invention, said preparation can rapidly in vivo with Acetaldehyde reacts and maintains the long period, and acetaldehyde is metabolized as innocuous substance and is excreted, and the present invention program combination preparation can be It is locally combined in long period and the acetaldehyde in human body of degrading, so that acetaldehyde keeps below harmful limit or is less than in vivo Content at least 30% or more when without using described pharmaceutical composition；Carrier in the present invention program is for controlling the acetaldehyde knot The rate of release of conjunction property substance, so that release time is at least 1 hour acetaldehyde-binding substances under one's belt.The present invention program combines Preparation there is good effect, combination preparation of the present invention to be applicable to reduce any approach in vivo the raised acetaldehyde of local metabolic The acetaldehyde concentration in source is used especially for reducing the uncomfortable reaction such as the gastrointestinal tract caused by drinking and nervous system, due to acetaldehyde Generation it is related with pick-me-up amount is drunk, therefore, it is horizontal that the present invention program can also promote alcohol user capacity for liquor, while the present invention Scheme can also reduce the probability that cancer occurs in oral cavity and alimentary canal.
Further, the acetaldehyde-binding compound includes but not limited to cysteine and its derivative and reduced form paddy The sweet peptide of Guang.
Preferably, the cysteine is L-cysteine or D-Cys.
Preferably, the cysteine derivative includes D, L- homocysteine and H- Cysteine-Glycines-OH.
Further, the probiotics with acetaldehyde metabolic capability be with aldehyde dehydrogenase activity, can be in human body It is colonized and the probiotics for internal acetaldehyde of degrading.
Preferably, the probiotics with acetaldehyde metabolic capability includes lactobacillus and Bifidobacterium.
Further, the lactobacillus includes Lactobacillus brevis and lactobacillus acidophilus；The Bifidobacterium includes two pairs of branch bars Bacterium and other Bifidobacteriums.
It is highly preferred that the probiotics with acetaldehyde metabolic capability is LGG.
Further, the Lactobacillus rhamnosus is to be preserved in American Type Culture collection warehousing (American type Culture collection, ATCC) bacterial strain, deposit number be ATCC 53103.
Further, the quality of the carrier is the 10~50%, preferably 15~40% of the combination preparation gross mass, More preferably 20~30%.
Further, the carrier is polymer soluble in the stomach.
Preferably, the carrier includes methacrylate derivative, chitosan, alginates, aluminium hydroxide, carbon Sour hydrogen sodium, sodium carboxymethylcellulose, sodium bicarbonate, carbomer and skim milk, more preferably methacrylate derivative, most Preferably Eudragit L and Eudragit S.
Preferably, the content of the sodium bicarbonate is the 10~30% of the carrier, preferably 20%.
Further, in the combination preparation, the quality of the acetaldehyde-binding compound is at least 500mg, the tool There is the quantity of the probiotics of acetaldehyde metabolic capability to be no less than 30,000,000,000 (3 × 1010CFU)。
As can be seen from the above description, the beneficial effects of the present invention are：Since acetaldehyde-binding substances are in the entire work of acetaldehyde It is released with sufficiently high level with period so that local acetaldehyde keeps relatively low, thus greatly reduces local acetaldehyde production Raw suffers from cancer risk.
Further, the dosage form of the combination preparation is tablet, capsule and/or particle.
Preferably, the preparation of the acetaldehyde-binding compound is formed as tablet, particle or capsule, described to have acetaldehyde generation The preparation for thanking to the probiotics of ability is formed as capsule.
The invention also includes the preparation methods of said combination preparation, and the preparation method comprises the following steps：
S1, the probiotics with acetaldehyde metabolic capability is used to microencapsulation, dry embedding techniques or double-layer embedment Technology is prepared into capsule preparations；
S2, the acetaldehyde-binding substances are prepared into coating tablet, granular preparation or capsule preparations；
S3, by with acetaldehyde metabolic capability after the step S1 and S2 operation processings probiotics and bind acetaldehyde object Matter mixes up to the combination preparation；
Wherein, the operation order of the step S1 and step S2 can be carried out at the same time, also interchangeable.
As can be seen from the above description, the advantageous effect of the present invention program is：The combination preparation is released with sustained release fashion under one's belt Acetaldehyde-binding substances are put, invention formulation is carried the combination preparation substance to stomach by carrier, then makes combination substance release. It is tablet, capsule or particle that reagent is whole or most of, and bind acetaldehyde is adhered to when it is wetted under the influence of hydrochloric acid in gastric juice Substance is in gastric mucosa or is formed in the content of stomach floating and agglomerates so that its residence time extension under one's belt, by This makes the release of drug and extends to the local action of stomach, by with acetaldehyde metabolic capability probiotics and bind acetaldehyde The control of substance preparation form, to the release of active ingredient in control combination preparation.For probiotics, microcapsules can be used Change, the key technology for the industrialization production that double-layer embedment technique is constituted；Microencapsulation protection technique efficiently solves oral process The inactivation of high temperature and strong acid gastric juice to probiotics；Using double-layer embedment microcapsules technology, be conducive to probiotics pass through it is oral The effect of gastric juice reaches stop field planting in enteron aisle, makes product is passed through to greatly improve compared with the similar product of market.
Further, the coating of the coating tablet is the polymer soluble in the stomach that can be hydrolyzed under one's belt.
Preferably, amount of the polymer soluble in the stomach in combination preparation gross mass is 5~20%.
Further, the granular preparation includes the acetaldehyde-binding substances being coated by clothing soluble in the stomach.
Further, the granular preparation further includes filler and adhesive.
Further, described adhesive is polymer soluble in the stomach, and the polymer soluble in the stomach can hydrolyze under one's belt and the stomach The quality of insoluble polymer accounts for the 2-5% of the granular preparation quality, it is preferable that the quality of the polymer soluble in the stomach is the particle The 3~4% of the quality of the pharmaceutical preparations.
Further, the component for including following weight point in the granular preparation：60 parts of acetaldehyde-binding substances, de- second 0~30 part of 10~40 parts of acyl chitin and calcium monohydrogen phosphate.
Preferably, the probiotics is prepared into capsule preparations using dry embedding techniques.
As can be seen from the above description, the beneficial effects of the present invention are：Dry embedding techniques and the breast not embedded under the conditions of Bacillus is compared to higher survival rate is maintained, therefore, bioactivity of the lactobacillus with stabilization of technology embedding, stomach juice-resistant, It is durable deposit, resistance to 60 DEG C of high temperature, and release is up to 84.5% in intestinal juice, suitable for being used in medicine, food.
Further, the preparation method further includes the preparation of probiotics powder, the preparation process of the probiotics powder It is as follows：
The probiotics viable bacteria body of S101, culture with acetaldehyde metabolic capability, and by the benefit with acetaldehyde metabolic capability Raw bacterium viable bacteria body is detached from culture solution；
S102, the step S101 isolated probiotics viable bacteria body with acetaldehyde metabolic capability through culture, fermentation, After concentration operation, after stabilizer, then freeze-dried operation is added, probiotics powder is obtained.
The invention also includes said combination preparation prepare relieve the effect of alcohol, protect liver, protect lung food, drug or health products and controlling Treat or prevent oral cavity, pharynx, oesophagus, stomach, lung, liver or large intestine cancer drug in purposes.
As can be seen from the above description, the advantageous effect of the present invention program is：Combination preparation of the present invention is applicable to containing a large amount of The consumer of alcoholic beverage is particularly suitable for those of ALDH2 low activities；Combination preparation of the present invention is also beneficial to consuming moderate quatity Pick-me-up consumer or consumption the consumer containing a small amount of alcohol or acetaldehyde food；It is additionally beneficial to smoker simultaneously； Due to containing a large amount of acetaldehyde in tobacco, in smoking process, acetaldehyde concentration steeply rises in human body upper digestive tract, the combination system Agent also has important protective effect, intestines can be protected by being embodied in addition to can effectively eliminate internal acetaldehyde in time to gastrointestinal tract Tract epithelial cell improves the integrality of gut barrier, adjusts immune response, reduces since harmful bacteria discharges lipopolysaccharides Level of endotoxin in blood caused by (lipopolysaccharide, LPS).Since smoking can lead to the mistake of human body Tiny ecosystem Weighing apparatus, causes microorganism harmful to health to increase, and beneficial flora is reduced, and therefore, combination preparation of the present invention can be in protect liver, shield lung Aspect has good effect.
The embodiment of the present invention one is：A kind of preparation method for the combination preparation that can reduce internal acetaldehyde concentration, specifically Include the following steps：
The preparation of S1, probiotics capsule preparation with acetaldehyde metabolic capability：It is described prebiotic with acetaldehyde metabolic capability Bacterium is Lactobacillus rhamnosus, and the Lactobacillus rhamnosus in the present invention program can generate a large amount of Lactobacillus rhamnosus by culture The method of viable bacteria body, the culture does not require particularly, as long as the Lactobacillus rhamnosus can be made to be proliferated, such as can With according to 107The viable bacteria body of Lactobacillus rhamnosus is inoculated in lactobacillus culture medium by the inoculum concentration of CFU/mL, and anaerobism, Under amphimicrobian or aerobic condition, after being cultivated 8-72 hours at a temperature of 15-38 DEG C, culture solution is obtained.The lactobacillus The culture medium for the various suitable lactobacillus cultures that culture medium can be known in the art, for example, can be milk and/or《Lactic acid Bacterium --- Basic of Biology and application》Lactic acid bacteria culturing medium described in (Yang Jiebin, light industry publishing house publish for 1996).
In present invention operation, the culture of Lactobacillus rhamnosus (LGG) ATCC 53103 is in lactic acid bacteria selective medium MRS It is carried out on agar plate.Incubator interior room is 5% H2, 10% CO2, 85% N2The oxygen-free environment that mixed gas is formed, 35 It is cultivated 72 hours under the conditions of DEG C.Bacterium is collected under anaerobic：It is clear with the concentration 100mM PBS (pH 7.4) restored in advance It washes three times.Bacterial suspension concentration is adjusted to 3 × 10 by Macfarlane turbidity standard (McFarland Standard)9CFU/ ml.(NOSOVA et al., (2000) Alcohol＆Alcoholism 35 (6):561-568).
The viable bacteria body of the Lactobacillus rhamnosus in above-mentioned culture solution is further detached, the method for the separation is not special Limitation as long as thalline can be enriched with from culture solution, such as can be realized by the method for centrifuging and/or filtering, described The condition of centrifugation and the filtering can be well known condition, and details are not described herein by the present invention.
The Lactobacillus rhamnosus thalline that above-mentioned lock out operation is obtained after culture in 6 hours, the pH value of culture solution Reduction amount is no more than 0.5, and buffer solution (for example, the sodium chloride of the sodium lactate of 86-90mmol/L, 0.5-0.9mmol/L, PH 5-5.5) in have higher self-dissolving rate (15% or more), also show higher aldehyde dehydrogenase activity.
The bacterium obtained is cultivated after the production operations such as the fermentation of standardization, concentration, the stabilizer of proper proportion is added, It the stringent production process such as is freezed and is freeze-dried, obtain the Lactobacillus rhamnosus powder dress of high activity and density.
Above-mentioned Lactobacillus rhamnosus powder is prepared into capsule preparations using dry embedding techniques.
The preparation of S2, acetaldehyde-binding substances tablet：NAC is mixed with calcium monohydrogen phosphate, the use of chitosan is viscous Mixture is pelletized, and the acetaldehyde-binding substances of granular preparation form are made.
Take 500g above-mentioned steps S2 treated NAC and the Lactobacillus rhamnosus capsule containing 30,000,000,000 Lactobacillus rhamnosus The combination preparation is obtained after preparation mixing.
Combination preparation made from aforesaid operations is taken to carry out external function test (external bacterial metabolism acetaldehyde ability test), tool Body is as follows：
1, it is measured by detecting the ability of the bacterial metabolism acetaldehyde in sealed tube
Experiment process is specially：Will include 450 μ l combination preparation suspension and mix 50 μ l 500 μM of acetaldehyde (eventually it is dense Degree) three parts of repeat samples, be incubated respectively under the conditions of 37 DEG C 0.5 hour, 1 hour.Another group is to have identical acetaldehyde concentration (500 μM) and without probiotics, the consistent control group one of other compositions is carried out at the same time, and test results are shown in figure 1.From Fig. 1 As can be seen that test group (LGG+NAC) can be realized the complete metabolism of acetaldehyde in 60min, and the acetaldehyde of control group one (NAC) Concentration also have close to half, and in same time the present invention program combination preparation metabolic capability much stronger than control group one.
2) external bacterial metabolism acetaldehyde ability detection is carried out in the case where there is ethyl alcohol existence condition
Concrete operations are as follows：In three containing 50 μ l combination preparations suspensions and 500 μM of acetaldehyde (final concentration) for mixing 50 μ l Part repeat samples containing (final concentration 22mM) or are free of ethyl alcohol, are incubated respectively under the conditions of 37 DEG C 0.5 hour, 1 hour, and with One it is carried out at the same time experiment as a control group not comprising the sample sets for having ethyl alcohol and acetaldehyde.Without containing bacterium, final concentration of 0.5M's The test control group set-up procedure of acetaldehyde standard preparation and/or ethyl alcohol (final concentration 22mM) is same as above.Non-genuine acetaldehyde in order to control It generates, reaction is terminated by the way that the 6mol/L perchloric acid of 50 μ l is added when experiment reaches time point.Ethyl alcohol and acetaldehyde quantify Analysis is detected (Jokelainen et al., (1996) Alcohol Clin Exp Res 20 by headspace gas chromatography (6):967-972.).Experimental group containing (final concentration 22mM) ethyl alcohol and control group, test results are shown in figure 2.It can by Fig. 2 To find out, (typical concentration for rear intestinal ethyl alcohol of drinking), test group (LGG+ in the presence of a certain concentration 22mM ethyl alcohol NAC it) is metabolized acetaldehyde ability in vitro with the comparison in reaction time with control group (NAC), test group (LGG+NAC) is in 60min The complete metabolism of same achievable acetaldehyde, and the acetaldehyde concentration of control group one (NAC) also has close to half, and in same time originally The metabolic capability of scheme of the invention combination preparation is much stronger than control group one.
2, in vivo functionality is tested
With usually alcohol tolerance, for the subject of 50g or so, (potable spirit amount reaches 50g and tipsy state occurs when drinking Person) combination preparation of the present invention is taken before drinking and drinks identical capacity for liquor (130ml, wine after taking placebo (starch capsule) Smart content is 50g) comparison, 25 subjects are counted respectively feels state of intoxication scoring as test result, statistical result As shown in figure 3, concrete outcome is as shown in table 1.
Table 1
The subject for the combination preparation for taking the present invention program it can be seen from Fig. 3 and table 1 is substantially at waking state, And the subject for taking placebo is then in state of intoxication.
Wherein, the state of intoxication refers to the self-assessment that subject drinks when completing to self-condition：From the sections 1-10 It scores, 1 representative is completely awake, and 10 representatives are completely drunk.
In the present invention program, the metabolic response of acetaldehyde is as follows：
Under the conditions of existing for acetaldehyde dehydrogenase：
NAD++CH3CHO+H2O→NADH+CH3COOH
NAC combined with acetaldehyde after reaction：
In conclusion a kind of combination preparation that can reduce internal acetaldehyde concentration provided by the invention and preparation method thereof with Purposes, the program are relieved the effect of alcohol or are promoted resistance to wine ability by reducing acetaldehyde concentration and can realize, have a good application prospect.
Example the above is only the implementation of the present invention is not intended to limit the scope of the invention, every to utilize this hair Equivalents made by bright specification and accompanying drawing content are applied directly or indirectly in relevant technical field, include similarly In the scope of patent protection of the present invention.

Claims (10)

1. a kind of combination preparation that can reduce internal acetaldehyde concentration, it is characterised in that：It is containing there are one or more including at least one kind The acetaldehyde-binding compound of a free sulfhydryl groups and amino, a kind of probiotics with acetaldehyde metabolic capability and a kind of carrier.
2. the combination preparation according to claim 1 that internal acetaldehyde concentration can be reduced, it is characterised in that：The acetaldehyde knot Conjunction property compound includes but not limited to cysteine and its derivative and reduced glutathione.
3. the combination preparation according to claim 1 that internal acetaldehyde concentration can be reduced, it is characterised in that：It is described that there is second The probiotics of aldehyde metabolic capability includes lactobacillus and Bifidobacterium.
4. the combination preparation according to claim 1 that internal acetaldehyde concentration can be reduced, it is characterised in that：The carrier Quality is the 10~50% of the combination preparation gross mass.
5. the combination preparation according to claim 1 that internal acetaldehyde concentration can be reduced, it is characterised in that：The carrier packet Include methacrylate derivative, chitosan, alginates, aluminium hydroxide, sodium bicarbonate, sodium carboxymethylcellulose, carbon Sour hydrogen sodium, carbomer and skim milk.
6. the combination preparation according to claim 1 that internal acetaldehyde concentration can be reduced, it is characterised in that：The combination system In agent, the quality of the acetaldehyde-binding compound is at least 500mg, the quantity of the probiotics with acetaldehyde metabolic capability No less than 3 × 1010CFU。
7. the combination preparation according to claim 1 that internal acetaldehyde concentration can be reduced, it is characterised in that：The acetaldehyde knot The preparation of conjunction property compound is formed as tablet, particle or capsule, and the preparation of the probiotics with acetaldehyde metabolic capability is formed For capsule.
8. a kind of preparation method of such as claim 1-7 any one of them combination preparations, it is characterised in that：The preparation method Include the following steps：
S1, the probiotics with acetaldehyde metabolic capability is used to microencapsulation, dry embedding techniques or double-layer embedment technique It is prepared into capsule preparations；
S2, the acetaldehyde-binding substances are prepared into coating tablet, granular preparation or capsule preparations；
S3, by with acetaldehyde metabolic capability after the step S1 and S2 operation processings probiotics and acetaldehyde-binding substances mix It closes up to the combination preparation；
Wherein, the operation order of the step S1 and step S2 can be carried out at the same time, also interchangeable.
9. the preparation method according to claim 8, it is characterised in that：The coating of the coating tablet be can in stomach water The polymer soluble in the stomach of solution.
10. it is a kind of as claim 1-7 any one of them combination preparation prepare relieve the effect of alcohol, protect liver, protect the food of lung, drug or Health products and the purposes in the drug for treating or preventing oral cavity, pharynx, oesophagus, stomach, lung, liver or large intestine cancer.
CN201810742665.8A 2018-07-09 2018-07-09 A kind of combination preparation that can reduce internal acetaldehyde concentration and preparation method thereof and purposes Pending CN108671232A (en)

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Application publication date: 20181019